This application seeks small grant support to investigate pesticide and metal exposures as risk factors for the development of Parkinson's disease (PD), and to examine how a background of genetic susceptibility may enhance the risk of PD in the presence of these exposures. The specific aims are: (i) to evaluate the association of occupational exposures to pesticides and metals with the risk of developing Parkinson's disease, and (ii) to estimate the individual and joint effects of pesticide and metal exposure with candidate genes that may modify the risk of developing PD. The original project was funded by NINDS, and we collected risk factor data and DNA from a well-characterized cohort of nearly 1500 incident PD cases and controls from a defined population (the Kaiser Permanente Medical Care Program of Northern California). This study used an extensive in-person questionnaire to assess general lifestyle, medical history, family history, use of tobacco products, residential history, alcohol and dietary information, and a detailed occupational history. Funding is requested to support the following activities: to enter data from more than 12,000 job modules for the PD cases and controls, and to analyze data regarding job tasks and occupational exposures that may influence the risk of developing PD. Blood samples were collected on 90% of the participants for genotyping of specific single nucleotide polymorphisms in candidate genes. Because there is considerable individual variability in the activity of xenobiotic enzymes that metabolize exogenous chemicals, it is plausible that the risk of developing PD after chemical exposure is modified by genetic susceptibility. To investigate this hypothesis, we propose to study a group of nine candidate genes in three major classes, including (i) genes involved in the transport or metabolism of dopamine, (ii) endogenous enzymes involved in xenobiotic metabolism and detoxification of toxicants, and (iii) genes associated with monogenic parkinsonism and potentially implicated in protein aggregation. By analyzing extensive information about pesticide and metal exposures with genetic polymorphisms from a group of carefully chosen candidate genes, we hope to advance knowledge regarding the genetic and environmental determinants of PD.